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  • [Show abstract] [Hide abstract]
    ABSTRACT: Epstein Barr virus (EBV) is a highly prevalent human gamma 1 lymphocryptovirus which infects both B lymphocytes and epithelial cells. In the healthy host, infection of these different cell lineages broadly reflects the different phases of the virus lifecycle. Memory B cells are the reservoir for latent EBV, in which viral gene expression is highly restricted to maintain an asymptomatic lifelong infection. In contrast, epithelial cells may be a major site of the virus lytic cycle, where infectious virus is propagated and transmitted via saliva to uninfected hosts. To achieve this dual tropism, EBV has evolved a unique set of glycoproteins in addition to a highly conserved set, which interact with cell lineage-specific receptors and switch cellular tropism during infection.
    02/2014; 4C:78-84. DOI:10.1016/j.coviro.2013.12.001
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    ABSTRACT: Background Malignant brain tumors in children generally have a very poor prognosis when they relapse and improvements are required in their management. It can be difficult to accurately diagnose abnormalities detected during tumor surveillance, and new techniques are required to aid this process. This study investigates how metabolite profiles measured noninvasively by (1)H magnetic resonance spectroscopy (MRS) at relapse reflect those at diagnosis and may be used in this monitoring process.Methods Single-voxel MRS (1.5 T, point-resolved spectroscopy, echo time 30 ms, repetition time 1500 ms was performed on 19 children with grades II-IV brain tumors during routine MRI scans prior to treatment for a suspected brain tumor and at suspected first relapse. MRS was analyzed using TARQUIN software to provide metabolite concentrations. Paired Student's t-tests were performed between metabolite profiles at diagnosis and at first relapse.ResultsThere was no significant difference (P > .05) in the level of any metabolite, lipid, or macromolecule from tumors prior to treatment and at first relapse. This was true for the whole group (n = 19), those with a local relapse (n = 12), and those with a distant relapse (n = 7). Lipids at 1.3 ppm were close to significance when comparing the level at diagnosis with that at distant first relapse (P = .07, 6.5 vs 12.9). In 5 cases the MRS indicative of tumor preceded a formal diagnosis of relapse.Conclusions Tumor metabolite profiles, measured by MRS, do not change greatly from diagnosis to first relapse, and this can aid the confirmation of the presence of tumor.
    Neuro-Oncology 12/2013; 16(1). DOI:10.1093/neuonc/not143
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    ABSTRACT: Background:Epithelial cell adhesion molecule is overexpressed in bladder tumours and released from bladder cancer cells in vitro. We test the hypotheses that urinary EpCAM could act as a biomarker for primary bladder cancer detection and risk stratification.Methods:Epithelial cell adhesion molecule was measured by ELISA in urine from 607 patients with primary bladder tumours and in urine from 53 non-cancer controls. Mann-Whitney tests and ROC analyses were used to determine statistical significance and discrimination between non-cancer controls and different stages and grades of disease. Multivariable modelling and Kaplan-Meier analyses were used to determine prognostic significance. The structure of urinary EpCAM was investigated by western blotting and mass spectrometry.Results:Urinary EpCAM levels increase with stage and grade of bladder cancer. Alongside grade and stage, elevated urinary EpCAM is an independent indicator of poor prognosis with a hazard ratio of 1.76 for bladder cancer-specific mortality. The soluble form of EpCAM in urine is the extracellular domain generated by cleavage between ala243 and gly244. Further studies are required to define the influence of other urinary tract malignancies and benign urological conditions on urinary EpCAM.Conclusion:The extracellular domain of EpCAM is shed into urine by bladder tumours. Urinary EpCAM is a strong indicator of bladder cancer-specific survival, and may be useful within a multi-marker panel for disease detection or as a stand-alone marker to prioritise the investigation and treatment of patients. The mechanisms and effects of EpCAM cleavage in bladder cancer are worthy of further investigation, and may identify novel therapeutic targets.British Journal of Cancer advance online publication, 28 November 2013; doi:10.1038/bjc.2013.744 www.bjcancer.com.
    British Journal of Cancer 11/2013; 110(3). DOI:10.1038/bjc.2013.744
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    ABSTRACT: Background: Prognostic biomarkers aim to improve on the current inadequate method of histological assessment to identify patients with oral epithelial dysplasia at greatest risk of malignant transformation. We aimed to assess the prognostic ability of six protein biomarkers linked to the epidermal growth factor receptor (EGFR) pathway, including three tetraspanins, in a large multicentre oral dysplasia cohort. Methods: One hundred and forty-eight cases with varying degrees of epithelial dysplasia underwent immunohistochemical assessment for CD9, CD151, CD82, EGFR, Her-2, and COX-2. Scoring was performed independently by two observers. Univariate analyses using both logistic and Cox regression models and a multivariate regression were performed. Results: Malignant progression was significantly greater in those cases with decreased expression of CD9 (P=0.02), and increased expression of CD151 (P=0.02), EGFR (P=0.04), and COX-2 (P=0.003). Histological grade (P=0.0002) and morphology (P=0.03) were also prognostic, whereas smoking and alcohol were not. The optimal combination by backward-variable selection was of histological grade (hazard ratio (HR) 1.64; 95% CI 1.12, 2.40), COX-2 overexpression (HR 1.12; 1.02, 1.24) and CD9 underexpression (HR 0.88; 0.80, 0.97). CD82 and Her-2 demonstrated no prognostic ability. Conclusion: This is the first study of the expression and prognostic potential of the tetraspanins in oral dysplasia. A combination of certain biomarkers with clinical factors appeared to improve the accuracy of determining the risk of malignancy in individuals with oral dysplasia. These findings may also offer potential new therapeutic approaches for this condition.
    British Journal of Cancer 11/2013; 109(11). DOI:10.1038/bjc.2013.600
  • Praxis 11/2013; 102(23):1427-9. DOI:10.1024/1661-8157/a001484
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    ABSTRACT: The cytogenetically cryptic t(5;11)(q35;p15) leading to the NUP98-NSD1 fusion is a rare but recurrent gene rearrangement recently reported to identify a group of young AML patients with poor prognosis. We used reverse transcription polymerase chain reaction (PCR) to screen retrospectively diagnostic samples from 54 unselected pediatric AML patients and designed a real time quantitative PCR assay to track individual patient response to treatment. Four positive cases (7%) were identified; three arising de novo and one therapy related AML. All had intermediate risk cytogenetic markers and a concurrent FLT3-ITD but lacked NPM1 and CEBPA mutations. The patients had a poor response to therapy and all proceeded to hematopoietic stem cell transplant. These data lend support to the adoption of screening for NUP98-NSD1 in pediatric AML without otherwise favorable genetic markers. The role of quantitative PCR is also highlighted as a potential tool for managing NUP98-NSD1 positive patients post-treatment. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 11/2013; 52(11). DOI:10.1002/gcc.22100
  • Journal of wound, ostomy, and continence nursing: official publication of The Wound, Ostomy and Continence Nurses Society / WOCN 11/2013; 40(6):565-6. DOI:10.1097/01.WON.0000436432.79769.2d
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    ABSTRACT: Cytomegalovirus (CMV) is a widely prevalent herpesvirus that is well tolerated by an immune competent host yet establishes a state of chronic infection. The virus is thought to undergo frequent subclinical episodes of reactivation which leads to an unusually large accumulation of CMV-specific CD8(+) T lymphocytes in the peripheral blood, a phenomenon termed "memory inflation." The high magnitude of the CMV T cell response has been implicated in impaired immunity to heterologous pathogens such as EBV, influenza and West Nile virus. Here, using murine CMV (MCMV), we show that memory inflation of virus-specific CD8(+) T cells is avoided if mice are infected with a replication defective virus called temperature-sensitive mutant 5 (tsm5), which carries an attenuating mutation within the DNA primase gene. Mice infected with tsm5 do generate primary T cell responses towards viral proteins but these do not amass to skew the memory repertoire of CD8(+) T cells. Therefore, attenuation of the virus replication machinery may be valuable in future CMV vaccine designs because the virus remains immunogenic but does not contribute to CMV associated T cell immune senescence. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 11/2013; 85(11). DOI:10.1002/jmv.23688
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    ABSTRACT: Formalin fixation, duration of tissue storage and tissue enrichment techniques can affect DNA methylation yield but these effects have not been quantitatively measured. The aim is to investigate the relative impact of these conditions on DNA methylation in rectal cancer. 10 rectal cancers with matched undissected fresh frozen tissues, laser capture microdissected (LCM) formalin-fixed paraffin-embedded (FFPE) tissues, manual macrodissected FFPE tissues, adjacent normal mucosa and stromal tissues were analysed for APC and LINE-1 methylation using bisulphite pyrosequencing. FFPE cancer tissues, which had been stored for at least 4years showed similar APC and LINE-1 methylation changes to matched fresh frozen cancer tissues. Laser capture microdissection did not increase the degree of methylation detected compared to manual macrodissection. Analysis of stromal tissues showed that they had undergone significant methylation changes compared to adjacent macroscopically normal mucosa, but not to the same extent as cancer tissues. Reliable DNA methylation results can be obtained from FFPE rectal cancer tissues, which have been in long-term storage. Because only minor differences in methylation between macrodissected and LCM cancer tissues were found, our results do not support the routine use of LCM to enrich for cancer cells for DNA methylation studies.
    Experimental and Molecular Pathology 10/2013; 95(3). DOI:10.1016/j.yexmp.2013.10.007
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    ABSTRACT: The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumour microenvironment which is composed of a variety of cell types, as well as non-cellular components such as collagen. Although HRS cells harbour oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumour microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal centre B cells, the presumed progenitors of HRS cells, up-regulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently over-express DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75, Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma cells from apoptosis and suggest an important contribution of the tumour microenvironment in promoting the oncogenic effects of EBV.
    Blood 10/2013; 122(26). DOI:10.1182/blood-2013-04-499004
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